Anxiolytic Property of Atypical Antipsychotics

描述（由申请人提供）：典型和非典型抗精神病药是用于治疗精神分裂症的主要药物。虽然两组对精神病显示出相似的疗效（例如，妄想，幻觉），目前还不清楚是否作为一类的药物具有内在的和上级典型的症状有关的动机，情绪和认知，独立于其有利的运动副作用。PI的长期目标是了解抗精神病药物作用的神经生物学和行为机制。本R21申请的目的是使用临床前方法来确定两种一线药物（利培酮和奥氮平）对恐惧和焦虑的行为和生理指标表现出抗焦虑作用的程度，作为广泛努力的一部分，以描述典型和非典型抗精神病药物对非精神病症状的重要差异。该项目假设是利培酮和奥氮平具有内在的抗焦虑特性，可以防止新的恐惧反应的发展，并消除现有的恐惧反应。本文将创新性地使用条件性回避反应模型来检验这一假设。该模型不仅具有抗“精神病”功效的高预测有效性，而且还包括反映恐惧和焦虑元素的多种可测量和非运动性反应（例如，体温、排便、排尿、超声波发声），这使得能够评估各种抗精神病药物的抗焦虑特性，同时仔细匹配它们的抗“精神病”功效并梳理出它们对学习或运动功能的作用的任何可能影响。其可靠性和敏感性将进一步验证高架十字迷宫（焦虑动物模型的金标准）。目的1是确定重复氟哌啶醇（典型），利培酮，奥氮平（非典型），利氮卓（抗焦虑药），西酞普兰（抗抑郁药与抗焦虑属性）治疗对获得各种条件性恐惧反应和条件性回避反应在这个模型中的行为影响。目标2将探讨它们对这些反应消退的影响。目的3将通过检查反复抗精神病药物治疗对高架十字迷宫（最广泛使用的焦虑动物模型之一）中各种焦虑指标的行为影响来验证这种新方法。该项目的创新之处在于，将使用单一的行为范式来同时识别药物的抗精神病和抗焦虑功效，而其他混杂因素（例如，药物对学习、记忆或运动功能的影响）受到严格控制。预计数据的可靠性很高，因为将直接比较各种剂量的典型和非典型药物与抗焦虑药物，并将收集多种恐惧/焦虑指标。此外，重复的药物治疗方案而不是急性治疗方案将提供临床治疗状况的更好建模。 该项目旨在揭示两种最广泛使用的非典型抗精神病药物利培酮和奥氮平在不同发展阶段缓解焦虑或恐惧的程度。这些发现有望对精神药物的开发和评价以及精神分裂症患者的治疗产生积极影响。

DESCRIPTION (provided by applicant): Typical and atypical antipsychotics are the primary drugs used to treat schizophrenia. Although both groups show similar efficacy against psychosis (e.g., delusions, hallucinations), it is unclear whether atypicals as a class have intrinsic and superior benefits over typicals on symptoms related to motivation, emotion and cognition, independent of their favorable motor side effects. The PI's long-term goal is to understand the neurobiological and behavioral mechanisms of action of antipsychotic drugs. The objective of this R21 application is to use a preclinical approach to identify the extent to which two first-line atypicals (risperidone and olanzapine) exhibit an anxiolytic effect on behavioral and physiological measures of fear and anxiety, as part of broad efforts to delineate the critical differences between typical and atypical antipsychotics on non-psychotic symptoms. The project hypothesis is that risperidone and olanzapine have an intrinsic anxiolytic property in preventing the development of new fearful reactions and in extinguishing existing ones. A conditioned avoidance response model will be innovatively used to test this hypothesis. This model not only has high predictive validity for anti-"psychotic" efficacy, but also encompasses multiple measurable and non- motoric responses reflecting elements of fear and anxiety (e.g., body temperature, defecation, urination, ultrasonic vocalization), which enable evaluation of the anxiolytic properties of various antipsychotics, while carefully matching their anti-"psychotic" efficacy and teasing out any possible influence from their effects on learning or motor functions. Its reliability and sensitivity will be further validated against the elevated plus maze (the gold standard of animal model of anxiety). Aim 1 is to identify behavioral effects of repeated haloperidol (typical), risperidone, olanzapine (atypical), chlordiazepoxide (anxiolytic), citalopram (antidepressant with anxiolytic property) treatment on the acquisition of various conditioned fear responses and conditioned avoidance responding in this model. Aim 2 will explore their effects on the extinction of these responses. Aim 3 will validate this novel approach by examining the behavioral effects of repeated antipsychotic treatment on various measures of anxiety in the elevated plus maze, one of most widely used animal models of anxiety. This project is innovative in that a single behavioral paradigm will be used to concurrently identify antipsychotic and anxiolytic efficacies of the drugs, while other confounding factors (e.g., drug effects on learning, memory or motor functions) are being carefully controlled. The reliability of the data is expected to be high because a wide range of doses of typical and atypical drugs will be compared directly with anxiolytic drugs and multiple measures of fear/anxiety will be collected. Furthermore, a repeated drug treatment regimen instead of an acute one will provide better modeling of the clinical treatment condition. This project is designed to reveal the extent to which the two most widely prescribed atypical antipsychotic drugs, risperidone and olanzapine, alleviate anxiety or fear at different stages of development. Such findings are expected to have a positive impact on the development and evaluation of psychotropic drugs and on the treatment of patients with schizophrenia.